This application is a competitive renewal for a K24 award "fMRI in Bipolar Illness." The applicant proposes to acquire training in functional connectivity analyses of fMRI data and in techniques that map brain functional (fMRI) data to brain structural (sMRI) data. Knowledge in these areas will be critical in further elucidating the functional (neural) circuit abnormalities in bipolar disorder and the anatomic basis, if any, for these neural abnormalities. Learning these techniques will broaden the applicant's expertise in neuroimaging and will allow her to be an even stronger mentor. The applicant proposes to work extensively with the Brain Mapping Division and Laboratory of Neuroimaging (LONI) at UCLA, as well as with offsite collaborators, to learn these cutting edge techniques for image analysis. Additionally, the applicant seeks to develop greater familiarity with neurocognitive tasks that can be adapted for use during fMRI scans, and to obtain basic familiarity with the field of molecular genetics. Greater understanding in these areas will guide her future research endeavors. The applicant proposes to 1) assess whether unmedicated euthymic bipolar subjects early in their course of illness have limbic (amygdala) hyperactivity and orbitofrontal hypoactivity (previously observed in treated patients while manic or euthymic);2) map functional scans to structural scans to explore the relationship of brain structure to these areas of activation or attenuation seen in fMRI and 3) use functional connectivity analyses to explore whether the normal (inhibitory) modulatory effects of prefrontal regions over the amygdala are dampened in the euthymic bipolar subjects compared to control subjects. Additionally, functional connectivity analyses will be conducted using the fMRI data obtained during the first K24 period, where patients were in the manic and depressed states. Bipolar illness is one of the top ten causes of disability worldwide, and effects 3% of the U.S. population. The neurophysiologic basis of this disorder remains unknown. Elucidating the functional neuroanatomic underpinnings of this disorder is a critical first step in developing targeted treatment.